- Email: [email protected]
Emergency Ross Procedure for Pediatric Aortic Valve Myxofibrosarcoma
Accepted Manuscript Emergency Ross procedure for paediatric aortic valve myxofibrosarcoma Mani Ram Krishna, FNB, Supreet P. Marathe, MCh, Amir Maghsoudi, MD, Geoffrey McCowage, FRACP, Megan C. Sherwood, FRACP, Yishay Orr, FRACS PII:
S0003-4975(18)31307-9
DOI:
10.1016/j.athoracsur.2018.07.060
Reference:
ATS 31909
To appear in:
The Annals of Thoracic Surgery
Received Date: 30 April 2018 Revised Date:
12 June 2018
Accepted Date: 1 July 2018
Please cite this article as: Krishna MR, Marathe SP, Maghsoudi A, McCowage G, Sherwood MC, Orr Y, Emergency Ross procedure for paediatric aortic valve myxofibrosarcoma, The Annals of Thoracic Surgery (2018), doi: https://doi.org/10.1016/j.athoracsur.2018.07.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Emergency Ross procedure for paediatric aortic valve myxofibrosarcoma
Authors: Mani Ram Krishna, FNB1
RI PT
Supreet P. Marathe, MCh1 Amir Maghsoudi, MD 2 Geoffrey McCowage, FRACP3
SC
Megan C. Sherwood, FRACP1,4
Institute: 1
M AN U
Yishay Orr, FRACS1,4
Heart Centre for Children, The Children’s Hospital at Westmead, Westmead NSW 2145, Australia.
2
TE D
Department of Pathology, The Children’s Hospital at Westmead, Westmead NSW 2145, Australia
3
Cancer Centre for Children, The Children’s Hospital at Westmead,
School of Child and Adolescent Health, Sydney Medical School,
AC C
4
EP
Westmead NSW 2145, Australia
University of Sydney, Sydney, Australia.
Running Title: Emergency Ross for aortic valve tumour Keywords: Ross procedure, cardiac tumours, sarcoma Word count: 1495
ACCEPTED MANUSCRIPT
Corresponding author:
Pediatric Cardiothoracic Surgeon Heart Centre for Children, The Children’s Hospital at Westmead, Cnr Hawkesbury Road and Hainsworth Street,
SC
Westmead NSW 2145, Australia.
RI PT
Yishay Orr, FRACS, PhD
Fax: +61 2 9845 2163
AC C
EP
TE D
[email protected]
M AN U
Phone: +61 2 9635 5325
ACCEPTED MANUSCRIPT Abstract: Primary cardiac tumours in children are uncommon and rarely demand surgical intervention. We report a malignant tumour arising from the aortic root in a five-year-old boy presenting with left ventricular outflow tract obstruction and tumour embolism, its surgical management
AC C
EP
TE D
M AN U
SC
RI PT
using the Ross procedure and the unique histopathological aspects of the tumour.
ACCEPTED MANUSCRIPT Primary cardiac tumours in children are rare, most are benign (1) and surgical intervention is rarely required. We report the case of a malignant cardiac tumour arising from aortic valve leaflets causing left ventricular outflow tract obstruction and peripheral embolism. This
RI PT
required emergency tumour resection and a Ross procedure.
SC
A previously well 5-year-old boy presented with acute onset of left leg pain and signs of limb ischaemia. Heart sounds were normal, but a grade 3/6 ejection systolic murmur radiating to
M AN U
the carotids was present.
Investigations including complete blood count, acute phase reactants, liver and renal function, coagulation and thrombophilia profile were normal. Doppler evaluation of the lower limbs
TE D
revealed a near occlusive thrombus in the left common femoral artery. The chest x-ray and electrocardiogram were normal.
EP
Transthoracic echocardiography demonstrated a bulky homogenous mass arising from the
AC C
right coronary cusp of a trileaflet aortic valve (Figure 1A-C) causing moderate obstruction to the left ventricular outflow tract (peak gradient 60 mm Hg, mean gradient 35mm Hg). Intracardiac anatomy was otherwise normal, with normal left ventricular dimensions, wall thickness, and function. There was trivial aortic regurgitation. The left coronary artery was visualized with normal flow on color Doppler whereas the right coronary artery was not identifiable.
ACCEPTED MANUSCRIPT A provisional diagnosis of aortic valve thrombus was established given there was no evidence of endocarditis and the child underwent urgent surgery to prevent further peripheral embolism. The ascending aorta was opened above the sinotubular junction and a large, lobulated gelatinous tumour was seen arising predominantly from the right coronary leaflet
RI PT
encasing both the aortic and ventricular aspects of the leaflet, the inter-coronary commissure and part of the left coronary leaflet (Figure 1D). The right coronary artery lumen was
SC
completely occluded by tumour until the second conal branch.
The tumour, aortic valve leaflets and proximal right coronary artery (RCA) were excised and
M AN U
the aortic annulus was debrided of tumour. The distal RCA was ligated and not revascularized as it had been completely occluded by tumor without evidence of myocardial ischemia. The left coronary artery button was harvested and the remainder of the aortic root was excised. A Ross procedure was utilized to reconstruct the aortic root with a 20-mm
TE D
bovine jugular valved conduit used to reconstruct the right ventricular outflow tract. A left femoral artery embolectomy was then performed. Histology of the embolus retrieved was
EP
consistent with tumour.
AC C
Histopathological examination of the tumour showed proliferation of atypical spindle cells in a variably myxoid stroma with significant nuclear atypia including hyperchromasia and plumed nuclei, high mitotic activity (up to 9 per 10 high power field (HPF) in the coronary artery and 3/10HFP in the aortic root) and areas of necrosis comprising 10-20% of the main tumour (Figure 2A-C). Tumour cells were positive for smooth muscle markers including smooth muscle actin (SMA) and desmin, and were negative for calretinin. The right coronary artery specimen showed complete occlusion of the lumen by tumour, and infiltration through the vessel wall into adjacent adipose tissue. The appearance was most consistent with a
ACCEPTED MANUSCRIPT myxofibrosarcoma as per the WHO classification of Tumours of the Lung, Pleura, Thymus and Heart (2).
Immunohistochemistry of the tumour revealed increased Platelet Derived Growth Factor
RI PT
Receptor A (PDGFRA) activity, and cytogenetics identified a novel PDGFRA-USP 8 fusion gene not previously reported. Post-operative recovery was uneventful. The patient was started on Sorafenib to reduce risk of recurrence. Whole-body Positron Emission Tomography
SC
performed 2 weeks after surgery and six months later did not show any residual tumour
AC C
EP
TE D
M AN U
activity, and the patient remains clinically well for more than one year post-operatively.
ACCEPTED MANUSCRIPT Comment: Primary cardiac tumours are rare in children. The incidence based on autopsy series is estimated at <0.1% (2). Pseudotumours including thrombus, vegetations and inflammatory masses are more common causes of an intra-cardiac mass. Approximately 90% of tumours
RI PT
are benign, and metastatic malignant tumours are about 20 times more common than primary malignancies (3). Angiosarcomas and rhabdomyosarcomas remain the commonest primary malignant cardiac tumours in children. An extensive literature search identified only one
SC
reported paediatric case of myxofibrosarcoma involving the aortic valve. Eisenstat and
colleagues reported on autopsy findings from a 5-year-old girl who died suddenly and was
M AN U
found to have an aortic valve mass demonstrating histopathology consistent with myxofibrosarcoma (4) . Our case is the first report of successful surgical and early adjuvant treatment of a paediatric aortic valve myxofibrosarcoma, a rare but important differential
TE D
diagnosis for an aortic valve mass.
Myxofibrosarcomas have previously been described as Myxoid Malignant Fibrous Histiocytoma, Myxoid Fibrosarcoma and Intimal Sarcoma; however these terminologies have
EP
been replaced in the recent WHO classification (5). Myxofibrosarcomas typically occur in
AC C
limbs of elderly individuals but primary cardiac involvement is well established. The left atrium is the most common cardiac site involved with clinical presentation due to interference with valve function, local invasion, systemic embolization or cachexia (6).
Myxofibrosarcoma is an aggressive tumour with poor response to chemotherapy and radiotherapy, and a high rate of recurrence (7). Management should involve complete resection of macroscopic tumour when feasible, including extensive resection of chamber walls or cardiac valves (7).
ACCEPTED MANUSCRIPT
Although the tumour is considered to be moderately sensitive to radiotherapy, the utility of chemotherapy and radiotherapy for myxofibrosarcoma is not well established. Cardiac radiotherapy has been associated with an acute risk of pericarditis, increased long-term risk
RI PT
of coronary artery disease, myocardial ischemia, and congestive cardiac. Consequently, risks of high dose local radiotherapy appeared to outweigh the benefits in our patient. Sorafenib, a multi-kinase inhibitor with activity against VEGFR and PDGFR, has been shown to be
AC C
EP
TE D
M AN U
there is very limited data in pediatric sarcomas.
SC
beneficial in tumors with PDFGR activity (8) with a favorable side effect profile, although
ACCEPTED MANUSCRIPT References: 1.
Becker AE. Primary Heart Tumors in the Pediatric Age Group: A Review of Salient Pathologic Features Relevant for Clinicians. Pediatric Cardiology. 2000;21(4):317-23. Nadas AS, Ellison RC. Cardiac tumors in infancy. Am J Cardiol. 1968;21(3):363-6.
3.
Tao TY, Yahyavi-Firouz-Abadi N, Singh GK, Bhalla S. Pediatric cardiac tumors:
RI PT
2.
clinical and imaging features. Radiographics. 2014;34(4):1031-46. 4.
Eisenstat J, Gilson T, Reimann J, Sampson B. Low-grade myofibroblastic sarcoma of
5.
SC
the heart causing sudden death. Cardiovasc Pathol. 2008;17(1):55-9.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to The
M AN U
2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol. 2015;10(9):1240-2. 6.
Shanmugam G. Primary cardiac sarcoma. Eur J Cardiothorac Surg. 2006;29(6):92532.
Ujihira K, Yamada A, Nishioka N, Iba Y, Maruyama R, Nakanishi K, et al. A case
TE D
7.
report of primary cardiac myxofibrosarcoma presenting with severe congestive heart failure. J Cardiothorac Surg. 2016;11(1):95.
EP
Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11:97.
AC C
8.
ACCEPTED MANUSCRIPT Figures: (1) Pre and intra operative images: (A) Transthoracic echocardiogram in Parasternal long axis (PLAX) view showing the homogenous mass involving the anterior aortic leaflet and extending into the aortic root (white arrow). (B) PLAX view with color Doppler. (C)
RI PT
Transthoracic echocardiogram in parasternal short axis (PSAX) view showing the mass
predominantly involving the right coronary cusp (white asterisk). (D) Intra operative photo showing the lobulated tumour mass visible through a transverse aortotomy (black arrow).
SC
(Ao=Aorta, LA=Left Atrium, LV=Left atrium, RA= Right Atrium, RV= Right Ventricle,
M AN U
RVOT=Right ventricular outflow tract)
(2) Histopathological examination (A) shows the spindle cell lesion involving the aortic wall. The stroma is variably myxoid (arrow) with adjacent fibrotic hypercellular areas. The attenuated tunica media of the aortic wall is apparent at the periphery (Hematoxylin and
TE D
Eosin (H&E) stain, x40 field). (B) Haphazardly arranged spindle cells in a loose stroma, some of which are atypical with hyperchromatic and more clumped nuclei. There are two mitotic figures (arrows) in this field (H&E stain, x200 field). (C) An area of necrosis adjacent
EP
to the spindle cell proliferation (H&E stain, x100 field) (D) Strong but focally positive
AC C
Desmin Immunoperoxidase staining of the spindle cell proliferation (x200 field)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0003-4975(18)31307-9
DOI:
10.1016/j.athoracsur.2018.07.060
Reference:
ATS 31909
To appear in:
The Annals of Thoracic Surgery
Received Date: 30 April 2018 Revised Date:
12 June 2018
Accepted Date: 1 July 2018
Please cite this article as: Krishna MR, Marathe SP, Maghsoudi A, McCowage G, Sherwood MC, Orr Y, Emergency Ross procedure for paediatric aortic valve myxofibrosarcoma, The Annals of Thoracic Surgery (2018), doi: https://doi.org/10.1016/j.athoracsur.2018.07.060. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Title: Emergency Ross procedure for paediatric aortic valve myxofibrosarcoma
Authors: Mani Ram Krishna, FNB1
RI PT
Supreet P. Marathe, MCh1 Amir Maghsoudi, MD 2 Geoffrey McCowage, FRACP3
SC
Megan C. Sherwood, FRACP1,4
Institute: 1
M AN U
Yishay Orr, FRACS1,4
Heart Centre for Children, The Children’s Hospital at Westmead, Westmead NSW 2145, Australia.
2
TE D
Department of Pathology, The Children’s Hospital at Westmead, Westmead NSW 2145, Australia
3
Cancer Centre for Children, The Children’s Hospital at Westmead,
School of Child and Adolescent Health, Sydney Medical School,
AC C
4
EP
Westmead NSW 2145, Australia
University of Sydney, Sydney, Australia.
Running Title: Emergency Ross for aortic valve tumour Keywords: Ross procedure, cardiac tumours, sarcoma Word count: 1495
ACCEPTED MANUSCRIPT
Corresponding author:
Pediatric Cardiothoracic Surgeon Heart Centre for Children, The Children’s Hospital at Westmead, Cnr Hawkesbury Road and Hainsworth Street,
SC
Westmead NSW 2145, Australia.
RI PT
Yishay Orr, FRACS, PhD
Fax: +61 2 9845 2163
AC C
EP
TE D
[email protected]
M AN U
Phone: +61 2 9635 5325
ACCEPTED MANUSCRIPT Abstract: Primary cardiac tumours in children are uncommon and rarely demand surgical intervention. We report a malignant tumour arising from the aortic root in a five-year-old boy presenting with left ventricular outflow tract obstruction and tumour embolism, its surgical management
AC C
EP
TE D
M AN U
SC
RI PT
using the Ross procedure and the unique histopathological aspects of the tumour.
ACCEPTED MANUSCRIPT Primary cardiac tumours in children are rare, most are benign (1) and surgical intervention is rarely required. We report the case of a malignant cardiac tumour arising from aortic valve leaflets causing left ventricular outflow tract obstruction and peripheral embolism. This
RI PT
required emergency tumour resection and a Ross procedure.
SC
A previously well 5-year-old boy presented with acute onset of left leg pain and signs of limb ischaemia. Heart sounds were normal, but a grade 3/6 ejection systolic murmur radiating to
M AN U
the carotids was present.
Investigations including complete blood count, acute phase reactants, liver and renal function, coagulation and thrombophilia profile were normal. Doppler evaluation of the lower limbs
TE D
revealed a near occlusive thrombus in the left common femoral artery. The chest x-ray and electrocardiogram were normal.
EP
Transthoracic echocardiography demonstrated a bulky homogenous mass arising from the
AC C
right coronary cusp of a trileaflet aortic valve (Figure 1A-C) causing moderate obstruction to the left ventricular outflow tract (peak gradient 60 mm Hg, mean gradient 35mm Hg). Intracardiac anatomy was otherwise normal, with normal left ventricular dimensions, wall thickness, and function. There was trivial aortic regurgitation. The left coronary artery was visualized with normal flow on color Doppler whereas the right coronary artery was not identifiable.
ACCEPTED MANUSCRIPT A provisional diagnosis of aortic valve thrombus was established given there was no evidence of endocarditis and the child underwent urgent surgery to prevent further peripheral embolism. The ascending aorta was opened above the sinotubular junction and a large, lobulated gelatinous tumour was seen arising predominantly from the right coronary leaflet
RI PT
encasing both the aortic and ventricular aspects of the leaflet, the inter-coronary commissure and part of the left coronary leaflet (Figure 1D). The right coronary artery lumen was
SC
completely occluded by tumour until the second conal branch.
The tumour, aortic valve leaflets and proximal right coronary artery (RCA) were excised and
M AN U
the aortic annulus was debrided of tumour. The distal RCA was ligated and not revascularized as it had been completely occluded by tumor without evidence of myocardial ischemia. The left coronary artery button was harvested and the remainder of the aortic root was excised. A Ross procedure was utilized to reconstruct the aortic root with a 20-mm
TE D
bovine jugular valved conduit used to reconstruct the right ventricular outflow tract. A left femoral artery embolectomy was then performed. Histology of the embolus retrieved was
EP
consistent with tumour.
AC C
Histopathological examination of the tumour showed proliferation of atypical spindle cells in a variably myxoid stroma with significant nuclear atypia including hyperchromasia and plumed nuclei, high mitotic activity (up to 9 per 10 high power field (HPF) in the coronary artery and 3/10HFP in the aortic root) and areas of necrosis comprising 10-20% of the main tumour (Figure 2A-C). Tumour cells were positive for smooth muscle markers including smooth muscle actin (SMA) and desmin, and were negative for calretinin. The right coronary artery specimen showed complete occlusion of the lumen by tumour, and infiltration through the vessel wall into adjacent adipose tissue. The appearance was most consistent with a
ACCEPTED MANUSCRIPT myxofibrosarcoma as per the WHO classification of Tumours of the Lung, Pleura, Thymus and Heart (2).
Immunohistochemistry of the tumour revealed increased Platelet Derived Growth Factor
RI PT
Receptor A (PDGFRA) activity, and cytogenetics identified a novel PDGFRA-USP 8 fusion gene not previously reported. Post-operative recovery was uneventful. The patient was started on Sorafenib to reduce risk of recurrence. Whole-body Positron Emission Tomography
SC
performed 2 weeks after surgery and six months later did not show any residual tumour
AC C
EP
TE D
M AN U
activity, and the patient remains clinically well for more than one year post-operatively.
ACCEPTED MANUSCRIPT Comment: Primary cardiac tumours are rare in children. The incidence based on autopsy series is estimated at <0.1% (2). Pseudotumours including thrombus, vegetations and inflammatory masses are more common causes of an intra-cardiac mass. Approximately 90% of tumours
RI PT
are benign, and metastatic malignant tumours are about 20 times more common than primary malignancies (3). Angiosarcomas and rhabdomyosarcomas remain the commonest primary malignant cardiac tumours in children. An extensive literature search identified only one
SC
reported paediatric case of myxofibrosarcoma involving the aortic valve. Eisenstat and
colleagues reported on autopsy findings from a 5-year-old girl who died suddenly and was
M AN U
found to have an aortic valve mass demonstrating histopathology consistent with myxofibrosarcoma (4) . Our case is the first report of successful surgical and early adjuvant treatment of a paediatric aortic valve myxofibrosarcoma, a rare but important differential
TE D
diagnosis for an aortic valve mass.
Myxofibrosarcomas have previously been described as Myxoid Malignant Fibrous Histiocytoma, Myxoid Fibrosarcoma and Intimal Sarcoma; however these terminologies have
EP
been replaced in the recent WHO classification (5). Myxofibrosarcomas typically occur in
AC C
limbs of elderly individuals but primary cardiac involvement is well established. The left atrium is the most common cardiac site involved with clinical presentation due to interference with valve function, local invasion, systemic embolization or cachexia (6).
Myxofibrosarcoma is an aggressive tumour with poor response to chemotherapy and radiotherapy, and a high rate of recurrence (7). Management should involve complete resection of macroscopic tumour when feasible, including extensive resection of chamber walls or cardiac valves (7).
ACCEPTED MANUSCRIPT
Although the tumour is considered to be moderately sensitive to radiotherapy, the utility of chemotherapy and radiotherapy for myxofibrosarcoma is not well established. Cardiac radiotherapy has been associated with an acute risk of pericarditis, increased long-term risk
RI PT
of coronary artery disease, myocardial ischemia, and congestive cardiac. Consequently, risks of high dose local radiotherapy appeared to outweigh the benefits in our patient. Sorafenib, a multi-kinase inhibitor with activity against VEGFR and PDGFR, has been shown to be
AC C
EP
TE D
M AN U
there is very limited data in pediatric sarcomas.
SC
beneficial in tumors with PDFGR activity (8) with a favorable side effect profile, although
ACCEPTED MANUSCRIPT References: 1.
Becker AE. Primary Heart Tumors in the Pediatric Age Group: A Review of Salient Pathologic Features Relevant for Clinicians. Pediatric Cardiology. 2000;21(4):317-23. Nadas AS, Ellison RC. Cardiac tumors in infancy. Am J Cardiol. 1968;21(3):363-6.
3.
Tao TY, Yahyavi-Firouz-Abadi N, Singh GK, Bhalla S. Pediatric cardiac tumors:
RI PT
2.
clinical and imaging features. Radiographics. 2014;34(4):1031-46. 4.
Eisenstat J, Gilson T, Reimann J, Sampson B. Low-grade myofibroblastic sarcoma of
5.
SC
the heart causing sudden death. Cardiovasc Pathol. 2008;17(1):55-9.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. Introduction to The
M AN U
2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. J Thorac Oncol. 2015;10(9):1240-2. 6.
Shanmugam G. Primary cardiac sarcoma. Eur J Cardiothorac Surg. 2006;29(6):92532.
Ujihira K, Yamada A, Nishioka N, Iba Y, Maruyama R, Nakanishi K, et al. A case
TE D
7.
report of primary cardiac myxofibrosarcoma presenting with severe congestive heart failure. J Cardiothorac Surg. 2016;11(1):95.
EP
Heldin CH. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun Signal. 2013;11:97.
AC C
8.
ACCEPTED MANUSCRIPT Figures: (1) Pre and intra operative images: (A) Transthoracic echocardiogram in Parasternal long axis (PLAX) view showing the homogenous mass involving the anterior aortic leaflet and extending into the aortic root (white arrow). (B) PLAX view with color Doppler. (C)
RI PT
Transthoracic echocardiogram in parasternal short axis (PSAX) view showing the mass
predominantly involving the right coronary cusp (white asterisk). (D) Intra operative photo showing the lobulated tumour mass visible through a transverse aortotomy (black arrow).
SC
(Ao=Aorta, LA=Left Atrium, LV=Left atrium, RA= Right Atrium, RV= Right Ventricle,
M AN U
RVOT=Right ventricular outflow tract)
(2) Histopathological examination (A) shows the spindle cell lesion involving the aortic wall. The stroma is variably myxoid (arrow) with adjacent fibrotic hypercellular areas. The attenuated tunica media of the aortic wall is apparent at the periphery (Hematoxylin and
TE D
Eosin (H&E) stain, x40 field). (B) Haphazardly arranged spindle cells in a loose stroma, some of which are atypical with hyperchromatic and more clumped nuclei. There are two mitotic figures (arrows) in this field (H&E stain, x200 field). (C) An area of necrosis adjacent
EP
to the spindle cell proliferation (H&E stain, x100 field) (D) Strong but focally positive
AC C
Desmin Immunoperoxidase staining of the spindle cell proliferation (x200 field)
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT